The evolutionary rates of hepatitis B virus (HBV) estimated using contemporary sequences are 10 2 to 10 4 times higher than those derived from archaeological and genetic evidence. This discrepancy makes the origin of HBV and the time scale of its spread, both of which are critical for studying the burden of HBV pathogenicity, largely unresolved. To evaluate whether the dual demands (i.e., adaptation within hosts and colonization between hosts) of the viral life cycle affect this conundrum, the HBV quasispecies dynamics within and among hosts from a family consisting of a grandmother, her 5 children, and her 2 granddaughters, all of whom presumably acquired chronic HBV through mother-to-infant transmission, were examined by PCR cloning and next-generation sequencing methods. We found that the evolutionary rate of HBV between hosts was considerably lower than that within hosts. Moreover, the between-host substitution rates of HBV decreased as transmission numbers between individuals increased. Both observations were due primarily to changes at nonsynonymous rather than synonymous sites. There were significantly more multiple substitutions than expected for random mutation processes, and 97% of substitutions were changed from common to rare amino acid residues in the database. Continual switching between colonization and adaptation resulted in a rapid accumulation of mutations at a limited number of positions, which quickly became saturated, whereas substitutions at the remaining regions occurred at a much lower rate. Our study may help to explain the time-dependent HBV substitution rates reported in the literature and provide new insights into the origin of the virus. IMPORTANCEIt is known that the estimated hepatitis B virus (HBV) substitution rate is time dependent, but the reason behind this observation is still elusive. We hypothesize that owing to the small genome size of HBV, transmission between hosts and adaptation within hosts must exhibit high levels of fitness trade-offs for the virus. By studying the HBV quasispecies dynamics for a chain of sequentially infected transmissions within a family, we found the HBV substitution rate between patients to be negatively correlated with the number of transmissions. Continual switching between hosts resulted in a rapid accumulation of mutations at a limited number of genomic sites, which quickly became saturated in the short term. Nevertheless, substitutions at the remaining regions occurred at a much lower rate. Therefore, the HBV substitution rate decreased as the divergence time increased. H epatitis B virus (HBV) is one of the most common infectious agents in the world. According to the World Health Organization (WHO), more than a third of the world's population (2 billion people) has been infected with HBV, and 240 million people among them are chronic carriers (1). Despite its importance, the evolutionary origins of HBV and the time scale of its spread remain elusive. For example, if the evolutionary history of HBV is calibrated using phylodynamic ph...

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Acute flares (AFs) of chronic hepatitis B usually occur during the immune-active stage (both immune clearance phase and immune reactivation phase), as the host immune system tries to control the virus. Successful host immune control over viral replication is usually presented as hepatitis B surface antigen seroclearance; however, 20–30% individuals with chronic hepatitis B may encounter repeated AFs with accumulative liver injuries, finally leading to the development of cirrhosis and hepatocellular carcinoma. AF can also develop in other clinical situations such as organ transplantation, cancer chemotherapy, and under treatment for chronic hepatitis B or treatment for chronic hepatitis C in patients with co-infected hepatitis B/hepatitis C. Understanding the natural history and immunopathogenesis of AF would help develop effective strategies to eradicate the virus and improve the clinical outcomes of patients with chronic hepatitis B. In this review article, the immunopathogenesis of AF, and the involvement of innate and adaptive immune responses on the development of hepatitis B flare will be briefly reviewed, with the emphasis on the role of cytokines and chemokines.

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